Common variable immune deficiency (CVID) is the most clinically important of the antibody deficiency diseases, but the molecular and genetic causes remain unknown. CVID B cells lack variable region somatic hypermutation, secrete immune globulins poorly, and fail to differentiate into plasma cells in vivo. Recently the lack of circulating memory CD27 + B cells has provided a means to classify patients and a potential opportunity to dissect the mechanisms leading to this disease. In addition to T cells, microenvironmental cues promote the generation and retention of memory. Factors such as antigen presenting cells expressing TNF related ligands, toll like receptor ligands and chemokines are critical to the retention of lasting B cell immunity. Defects in any of these factors may contribute to the memory cell deficiency seen in CVID. Specific Aim 1a of this Project will investigate the biologic relevance of memory B cells as a disease marker potentially related to antibody production in vivo and in vitro. For normal B cells, selective triggering by dendritic cells or microbial antigens supplies an antigen independent mechanism to long term B cell memory; thus Specific Aim 1b will investigate if these signals are operative, evaluating the role of toll like receptors, TNF related ligands, and antigen presenting cells in CVID B cell maturation. Specific Aim 2, will investigate the chemokine and chemokine receptor status of CVID B cells, and determine if the chemotactic signals required for B cell migration and differentiation, are functional. Since a mutation of CXCR4 leads to a B cell defect similar to CVID, defects in chemokine pathways could lead to loss of functional B cells and B cell memory, due to a lack of exposure to an essential environmental signal. Due to recent advances in understanding specific stages of B cell biology, this Project, based on a large and well characterized patient population, can elucidate selected stages in which B cell memory and differentiation are blocked in CVID.